Film-forming compositions for enveloping solid forms, particularly pharmaceutical or food products or seeds, and products obtained, coated with said compositions

ABSTRACT

The present invention relates to film-forming compositions for enveloping solid forms such as pharmaceutical or food products or seeds, wherein they comprise, by weight: 
     15 to 85% of a cellulosic film-forming substance, 
     10 to 70% of at least one alpha-cellulose, 
     5 to 30% of at least one plasticizer suitable for consumption.

The present invention relates to film-forming compositions forenveloping solid forms, particularly pharmaceutical products, foodproducts or seeds; it also relates to a process for enveloping with theaid of said compositions and to the products obtained, coated with saidcompositions.

Dry pharmaceutical forms and certain food products, for example tablets,are made by agglomerating particles comprising excipients and activeingredients.

This agglomeration is generally obtained by the conventional process ofgranulation, compacting and compression.

In order to protect the dry forms against degradation of the activeingredients by the action of light or by oxidation, against abrasionwhen packing in blisters, against the formation of dust, said dry formsare covered with a film of an enveloping agent.

This technique is well known in the confectionery or pharmaceuticalindustry, with sugar-coating, coating with shellac in an alcohol medium,called "gumming", and film-forming vinylic, acrylic or cellulosicvarnishings.

Similarly, it has already been recommended to envelop various grains andparticularly seeds; such an envelope facilitates manipulation of theproducts and improves the behaviour of these seeds when they areplanted.

These envelopes isolate the dry forms and enable them to be identified,for example, by simple surface coloration.

Sugar-coating is a long, expensive operation.

Filming, effected in an organic solvent medium, is a more rapid andeconomical, manual or automatized technique, but the use of alcohols orchlorinated solvents renders it dangerous.

Various products and various techniques have recently been proposed formaking film envelopes in an aqueous medium. These processes arecharacterized by the use of hydrosoluble or hydrodispersiblefilm-forming substances which are generally applied by spraying on thedry forms in rotation in a turbine or in lift in a fluidized air bed.

The use of water as solvent or dispersant of the film-formingsubstances, is economical with respect to the organic solvents; however,it is limiting from the following standpoints:

extended evaporation time,

low concentration of the film-forming agent in solution or dispersion inthe enveloping formulations,

sensitivity of the dry form and of the active ingredient to the aqueousmedium, which may provoke disintegration of the form or decomposition ofthe active ingredient.

It is an object of the present invention to avoid the above drawbacks byproducing novel film-forming compositions and applying them to theenveloping of solid forms.

The film-forming compositions for enveloping according to the presentinvention are characterized in that they contain:

from 15 to 85% by weight of a cellulosic film-forming substance,

from 10 to 70% by weight of at least one alpha-cellulose,

and from 5 to 30% by weight of a plasticizer suitable for consumption.

The cellulosic film-forming substance used is a known product previouslyrecommended for making envelopes. It is known that, from the knowncellulosic derivatives, the alkyl ethers of cellulose, thehydroxyalkylethers of cellulose, the monocarboxylic esters of celluloseand the mixed ether-esters of cellulose, may be used. From theseproducts, particular mention will be made, as cellulosic derivativeswhich may be used, of the hydroxypropylmethylcelluloses and moreespecially hydroxypropylmethylcelluloses which present a low viscosity(i.e. a viscosity of 3 to 15 centipoises, at ambient temperature, in asolution at 2% by weight in water).

Contents of film-forming substance less than 15% are insufficient tomake a continuous film. In that case, the envelope, as seen byexamination by microscope, is a simple juxtaposition of particles.

On the other hand, with contents of film-forming substances greater than85%, the envelope formed does not differ significantly from what is madein the prior art.

A plasticizer suitable for consumption will be used with this cellulosicfilm-forming substance. There again, the use of plasticizers in thevarious applications of cellulosic film-forming substances is known. Theessential function of the plasticizers that may be used is not to lowerthe melting point of the cellulosic polymers, but they serve to modifythe suppleness and strength of the films made with these cellulosicsubstances.

The plasticizer required in the present invention may be a hydrophilicor hydrophobic product suitably selected to improve the suppleness ofthe film made.

Hydrophilic plasticizers make it possible to obtain films which arerapidly disintegrated in an acid medium or in water.

A food or pharmaceutical polyol of the type; glycerine, propyleneglycol, polyethylene glycol, sorbitol or saccharose, will preferably beselected.

Hydrophobic plasticizers make it possible to obtain films of whichdisintegration is delayed or which prolong masking of the taste.

The latter will be selected from conventional fatty substances, such asacids, alcohols, fatty esters and derivatives thereof or phthalates,citrates or sebacates of ethyl or butyl.

Preference will be given to a hydrodispersible plasticizer of thepolyethyleneglycol ester type, for example the stearate ofpolyoxyethylene 300, which will facilitate dispersion of the proposednew film-forming composition in the solvent of preparation.

Said plasticizers and their various functions vis-a-vis the propertiesof the films obtained have already been described or suggested invarious publications.

The content of hydrophilic plasticizer, for example polyethyleneglycol6000, is preferably at least 10% by weight with respect to the dryfilm-forming substance.

The content of hydrophobic or hydrodispersible plasticizer, for examplethe stearate of polyoxyethylene (8), is preferably at least 15% byweight with respect to the dry film-forming substance.

A plasticizer content of more than 30% in the novel film-formingcomposition modifies the mechanical properties of the envelope whichbecomes fragile. Engravings and lines for breaking the tablets are thenmasked by a film which is too covering.

The third essential constituent of the invention is an alpha cellulose.It has already been indicated that alpha cellulose was capable, thanksin particular to its aptitude to create hydrogen bonds with othermaterials, of performing a role of "binding agent" vis-a-vis for exampleproducts with OH functions and in Particular cellulosic derivatives.According to the present invention, from 10 to 70% by weight of alphacellulose will therefore be used in the mixtures. Alpha cellulose isunderstood to mean the alpha celluloses of various types known at thepresent time; for example, it is known that the alpha cellulosesobtained by mechanical grinding of natural alpha celluloses or the alphacelluloses obtained by partial depolymerization (made by acid or basichydrolysis) of natural alpha cellulose, may be used according to theinvention. Moreover, this alpha cellulose performs an important role ineffecting a good adherence of the coating film on the core which(particularly in the case of pharmaceutical cores) generally containsproducts such as starch, cellulose or cellulosic derivatives, sugars,etc. . .

To obtain a good dispersion of this alpha cellulose in the mixturesaccording to the invention, it is desirable that this product be used inthe form of a fine powder with a mean granulometry of less than 100μ andpreferably of less than 50μ.

An alpha cellulose content of less than 10% does not give a bindingpwere sufficient to modify the film-forming substance, and the film doesnot adhere well to the substrate.

When the alpha cellulose content exceeds about 70% by weight of themixture, a film of insufficient pliability is obtained.

The compositions according to the invention may further comprise theknown additives conventionally used for modifying the properties of thecoating material (colour, speed of dissolution in various media), andfor protecting said material (anti-oxidant, anti-ultra-violet, . . . ).

The preferred process for making a coating using film-formingcompositions according to the present invention consists in dissolvingor dispersing the various ingredients of the mixture in a suitablesolvent such as an aqueous medium then in spraying the solution (orsuspension) obtained onto previously prepared cores.

The aqueous solutions (or dispersions) may attain concentrations of upto 25% by weight of composition according to the invention, whichenables coatings to be made in a short period (15 mins. for example).

The films obtained are very covering and adhere strongly to the solidsubstrate.

Consequently, they present an excellent resistance to abrasion or topeeling at sharp edges, marks for breaking the pharmaceutical tablets orat engravings thereon.

The hardness of the cores coated with these novel film-formingcompositions is particularly increased, this avoiding friabilitythereof.

The choice of the film-forming composition used and of the additives tothis composition will depend on the applications envisaged.

For example, by using the compositions according to the invention, it isthus possible, in food or pharmaceutical applications, to modify or maskthe taste of bitter active ingredients that the products may present;moreover, it is particularly easy to make forms where the activeingredients that they contain have delayed release.

Similarly, in the case of coating seeds, an effective protection againstdampness may be obtained, whilst maintaining (or even improving) thegerminative properties of said seeds; compositions allowing coating atlow temperature will be used for this application.

The following non-limiting examples illustrate the invention.

EXAMPLE 1

500 g of hydroxypropylmethylcellulose (HPMC), quality 6 centipoises, areintroduced into an ERWEKA laboratory mixer. 2000 g of pulverulentalpha-cellulose with a granulometry of 20μ are added thereto.

The mixture is mixed at slow speed for 9 mins. to obtain a homogeneousmass of powder.

This powder is then wetted with 1000 g of a 50% aqueous solution ofpolyethyleneglycol 6000, the latter being added in small portions andmechanical stirring being maintained.

The humid mass is transformed into small compact agglomerates orgranules after a mixing time of from 10 to 15 mins. These agglomeratesare calibrated over an oscillating Frewitt grid.

These agglomerates are deposited on drying sieves in a ventilated oventaken to 60° C. until the humidity has evaporated.

2955 g of dry granules, called product A, having a residual watercontent of 4 to 5% maximum, are then recovered.

These granules are sieved in order to conserve the 20 to 200μ fraction,the fines being recycled in the mixer.

A series of tests is carried out on product A in order to measure itsfilm-forming properties.

(a) Dispersion

A dispersion (1) of 220 g of product A in 780 g of water is prepared at40° C. by slow mechanical stirring (500 r.p.m.) using a laboratoryRAYNERI. A fine, homogeneous dispersion is obtained in 15 mins.

By comparison, a dispersion (2) of 100 g ofhydroxypropylmethylcellulose, 6 cP, in 900 g of water at 40° C. by thesame system and at the same speed requires more than 30 mins. Thedispersion presents lumps and it is necessary to disperse suchaccumulations which increase the speed of stirring to more than 2000r.p.m. to homogenize dispersion (2).

(b) Characteristics of the dispersion

Dispersion (1) of product A is in the form of hardly viscous liquid,flowing freely and whitish.

The dry matter content is 21.8% (3 hours at 105° C.).

The microscopic appearance of dispersion (1) presents colloidalparticles.

Spreading of dispersion (1), with an inside micrometer caliper 50μ, on aglass plate shows the absence of solid particles to the naked eye.

(c) film-forming properties of product A

Dispersion (1) lends itself easily to spraying with a gun of the"Airspray" type of trademark Binks, model 960, fitted with a 1 mm nozzleand supplied at an air pressure of 3.5 kg.

A thin film of product A is formed on a glass plate by spraying thesolution (1) thereon until a thickness of 20μ is obtained after dryingof the plate in the air at 60° C.

This film is translucent and is easily detached from the glass plate. Itis supple and not brittle.

EXAMPLE 2

(a) Composition

    ______________________________________                                        Hydroxypropylmethylcellulose (6 cP) (HPMC)                                                               42                                                 Cellulose (20μ )        35                                                 PEG 400                    10                                                 TiO.sub.2 - titanium oxide  8                                                 Aluminic lake of Erythrosine colorant                                                                     5                                                 ______________________________________                                    

(b) Preparation

8.2 kg of hydroxypropylmethylcellulose, 6 cP, and 7 kg ofmicrocrystalline cellulose of 20μ are introduced into a Lodigegranulator.

The wetting liquid comprising 2 l of water, 2 kg of PEG 400, 1.6 kg oftitanium oxide, 1 kg of aluminic lake Erythrosine and 2 kg of 10%aqueous solution of hydroxypropylmethylcellulose, 6 cP, or 200 g ofhydroxypropylmethylcellulose, is prepared.

The wetting liquid is mixed on a rapid disperser then ground.

The wetting liquid is added slowly in the mixer on the powder mixture inmotion.

A regular pink grain is formed.

The wet grain is calibrated over a 1 mm Frewitt grid, dried over a bedof fluidized air then sieved again.

The granulous powder obtained has a density of about 0.5. It is ofuniform pink colour.

(c) Use

200 g of this preparation are added to 800 g of cold water; ahomogeneous dispersion is obtained after about 20 mins.

This preparation enables 10 kg of tablets to be coated in 25 mins. in aforced ventilation 24" diameter turbine.

EXAMPLE 3

20 kg of hydroxypropylmethylcellulose, 6 cPs, and 16 kg ofmicrocrystalline cellulose with a mean granulometry of 20 microns areintroduced into a DIOSNA mixer-granulator.

The powders are mixed for 5 minutes.

On the other hand, 20 liters of an aqueous dispersion D, composed of 4kg of polyoxyethylene stearate 8 and 16 l of water are prepared.Dispersion is effected at 45° C.

The aqueous dispersion D is progressively introduced into the rotatingmixer. At the end of the introduction, granulation is continued for 7minutes.

The granulate thus obtained is of regular granulometric dimensionscomprised at 95% between 100 and 1000 microns.

The granulate is dried over a plate oven up to a residual humidity of2%.

Granulate D thus obtained keeps perfectly.

It is easily dispersed at ambient temperature in water, in water-alcoholmixtures on condition that the latter have a minimum water content of15%, as well as in mixtures of alcohols-chlorinated solvents (forexample dichloromethane). Total dispersion at a concentration of 15% to20% is obtained with weak stirring in 20 minutes in water and thewater-alcohol (methylic, ethylic or isopropylic) mixtures.

Under the same conditions, the hydroxypropylmethylcelluloses such asMethocel B5 require violent stirring.

The formation of lumps which are difficult to dissolve afterwards orwhich require a rest time of 12 to 24 hours, is provoked.

EXAMPLE 4 (Industrial Use)

A-Equipment

60" Manesty Accelacota turbine,

4 Walter WA 15 spray guns,

with 1 mm diameter spray nozzles.

Tablets

0.220 kg of engraved placebos: Lactose Fast Flow ®/Avicel®/magnesiumstearate (49.7/49.7/0.6) of 10 kg hardness.

A dispersion for coating is prepared, composed as follows: 3.2 kg of thegranulate G obtained in Example 3 are introduced into 14.4 liters ofwater with moderate stirring. Stirring is maintained for 25 minutes. 2.4kg of SEPISPERSE AP 3012 * are added to this dispersion.

Characteristics of the pigmentary suspension:

    ______________________________________                                        pigment content    35%                                                        HPMC content        2%                                                        propyleneglycol content                                                                          30%                                                        ______________________________________                                    

After mixture, the dispersion for coating is ready for use. Itsviscosity is 800 cPs. Its dry matter content is 20.4%.

Operational parameters

1. Preheating of the tablets to 40° C.

2. For 3 minutes:

    ______________________________________                                        Rotation of the turbine                                                                           3 r.p.m.                                                  air intake temperature                                                                            80° C.                                             rate of spray       250 g/minute/gun                                          spray pressure      4 kg/cm.sup.2                                             ______________________________________                                    

3. For 20 minutes:

    ______________________________________                                        rotation of the turbine                                                                           6 r.p.m.                                                  air intake temperature                                                                            80° C.                                             rate of spray       170 g/minute/gun                                          spray pressure      4 kg/cm.sup.2                                             ______________________________________                                    

Total quantity sprayed: +16.6 kg, or in dry product: 16.6×20.4% =3.78kg.

Average weight gain of the tablets: 1.5%.

Regular coating of satin appearance.

Total spray time: 23 minutes.

B By way of comparison, a conventional formulation based on HPMC, 6 cPs,is made under the same conditions of equipment, charge and tablets.

3.2 kg of Pharmacoat 606 are introduced with violent stirring in 29liters of water. Violent stirring is maintained for 30 minutes, then thesolution is left to stand for 12 hours. 2.4 kg of SEPISPERSE AP 3012 arethen introduced into this dispersion and the mixture is homogenized. Theviscosity of the coating dispersion, ready for use, is 800 cPs,identical to the preceding test, for a solid matter content in thedispersion of 11.5%.

Operational Parameters

1. Preheating of the tablets at 40° C.

2. For 50 minutes:

    ______________________________________                                        rotation of the turbine                                                                            5 r.p.m.                                                 air intake temperature                                                                             150° C.                                           rate of spray        4 g/minute/gun                                           spray pressure       4 kg/cm.sup.2                                            ______________________________________                                    

It is impossible to increase the liquid flowrate as there is a risk ofadhesion.

Quantity sprayed: 600 g×50=30 kg, or 3.45 kg of dry product.

Average weight gain of the tablets: 1.5%.

Regular coating of appearance slightly more shiny than in the previousexample.

Saving in spray time: 54%.

Saving in time on the complete operation: 35%.

EXAMPLE 5

Granulate G obtained in Example 3 is used for coating tablets ofpancreas hydrolysate under the following conditions:

tablets of 400 mg composed of extract of pig's pancreas (250 mg) and ofexcipients (Lactose Fast Flo/Ac di sol). They are obtained by the doublecompression technique and have a hardness of 3 kg.

quantity of tablets: 25 kg.

coating dispersions:

    ______________________________________                                        granulate G           600    g                                                Sepisperse K 3011     400    g                                                ethanol 95            3000   g                                                water                 750    g                                                ______________________________________                                    

600 g of granulate G are introduced into a water-ethanol mixturecomposed of 750 g of water and 3000 g of 95° ethanol, with stirring.Stirring is maintained for 17 minutes, then 400 g of a pigmentarydispersion in an alcohol medium with a solid content of 45% are added,and the mixture is homogenized.

Equipment

conventional sugar-coating turbine with a capacity of 40 kg.

2 air spray Binks 460 guns.

Operational parameters

No preheating

Spray pressure: 3 kg/cm²

Liquid flowrate: 40 g/minute/gun

Duration: 1 hour

Temperature of the tablets maintained between 25° and 30° C.

Results

Regular coating of satin appearance.

Weight gain of the tablets: 2.5%.

Hardness after coating: 10 kg. or an increase of 7 kg over plaintablets.

What is claimed is:
 1. A process for enveloping solid forms such aspharmaceuticals, food products or seeds with a film-forming composition,comprising the steps of:making a solution or dispersion of thecomponents of a film-forming composition comprising, by weight, 15 to85% of a cellulosic film-forming substance, 10 to 70% of at least onealpha-cellulose, and 5 to 30% of at least one plasticizer suitable forconsumption; and spraying said solution or dispersion on the form to beenveloped.
 2. A process as in claim 1, wherein said solution ordispersion is in an aqueous medium.
 3. A process as in claim 1, whereinsaid cellulosic film-forming substance is selected from the groupconsisting of the alkylethers of cellulose, the hydroxyalkylethers ofcellulose, the monocarboxylic esters of cellulose, and the mixed etheresters of cellulose.
 4. A process as in claim 3, wherein said cellulosicfilm-forming substance is a hydroxypropylmethylcellulose of lowviscosity.
 5. A process as in claim 1, wherein said alphacellulose isadded in the form of a powder with a granulometry of less than 100microns.
 6. A process as in claim 5, wherein said alphacellulose isadded in the form of a powder with a granulometry of less than 50microns.
 7. A process as in claim 1, wherein said plasticizer isselected from the group consisting of polyethyleneglycol and thestearate of polyoxyethylene.
 8. A process as in claim 2, wherein saidsolution or dispersion contains up to about 25% by weight of saidfilm-forming composition.